Search

Dit overzichtsartikel wil het klinisch potentieel aantonen van Automatische Impedantie Manometrie (AIM) als nieuwe, nietradiologische techniek voor screening en diagnostiek van faryngale dysfagie, zijnde slikstoornissen in de mond, keelholte en bovenste slokdarm. Deze AIM-techniek maakt gebruik van een katheter met druksensoren en impedantie-elektroden om slikken kwantitatief te beschrijven. Een geïntegreerde – eerder dan afzonderlijke – analyse van de gemeten druk- en impedantiepatronen die ontstaan bij het doorslikken van een voedselbolus, kan een zinvolle aanvulling zijn op de dynamische beeldvormingsonderzoeken die vandaag de dag als gouden standaard worden gezien. Belangrijke voordelen zijn het objectieve karakter van de techniek en de geautomatiseerde berekening van diverse slikparameters. Een globale maat voor de slikfunctie kan worden bekomen (Slik Risico Index, SRI) en houdt verband met (de ernst van) het aspiratierisico van de patiënt en de aanwezigheid van bolusresidu. Zo kan een accurate detectie van aspiratie met een sensitiviteit van 0,88 en specificiteit van 0,96 niet via radiologisch onderzoek bereikt worden. Verschillende slikparameters zijn ook voldoende gevoelig om veranderingen in voedselconsistentie te detecteren en om de effecten van slikmanoeuvres objectief te beschrijven. Recent werd ook aangetoond dat deze AIM-analyse snel en betrouwbaar kan worden uitgevoerd door clinici met variërende ervaring en opleiding. Bovendien worden in verschillende patiëntengroepen andere patronen van afwijkende slikparameters aangetroffen. Of deze observatie aanleiding kan geven tot specifieke slikdiagnoses en dus meer gerichte behandelingen is momenteel onderwerp van onderzoek.

Ouderen worden vaak geconfronteerd met slikproblemen. Het is hierbij van belang een onderscheid te maken tussen enerzijds presbyfagie, dit is de invloed van het primair verouderingsproces op de slikfunctie en anderzijds dysfagie, zijnde een pathologische slikstoornis die wordt veroorzaakt door ouderdomsgerelateerde ziekteprocessen en hun behandeling. In dit literatuuroverzicht ligt de focus op presbyfagie. Hierbij wordt de impact van het natuurlijk verouderingsproces op de orofaryngeale slikfunctie en op andere lichaamsfuncties die indirect gerelateerd zijn aan het slikken besproken. Uit de literatuur blijkt dat bij het primair verouderen een aantal functies bewaard blijven, een aantal functies deterioreren, een aantal compensatoire mechanismen in werking treden, maar dat de slikveiligheid als dusdanig behouden blijft. De tekst sluit af met implicaties voor de klinisch praktijk, met name een aantal adviezen rond de detectie van slikstoornissen bij ouderen en een aantal preventieve maatregelen voor gezonde ouderen.

Abstract Activation of inflammatory pathways is known to accompany development of obesity-induced nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive proinflammatory mediators interleukin (IL)-1β and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In this study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human α-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin-resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3-deficient mice showed strongly reduced levels of lipids in the liver after being fed a high-fat diet. Moreover, these mice were resistant to high-fat-diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1−/− mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with α-1 antitrypsin during the last 10 d of a 16-wk high-fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential.

Innate immunity plays a pivotal role in obesity-induced low-grade inflammation originating from adipose tissue. Key receptors of the innate immune system including Toll-like receptors-2 and -4 (TLRs) are triggered by nutrient excess to promote inflammation. The role of other TLRs in this process is largely unknown. In addition to double-stranded viral mRNA, TLR-3 can also recognize mRNA from dying endogenous cells, a process that is frequently observed within obese adipose tissue. Here, we identified profound expression of TLR-3 in adipocytes and investigated its role during diet-induced obesity. Human adipose tissue biopsies (n=80) and an adipocyte cell-line were used to study TLR-3 expression and function. TLR-3-/- and WT animals were exposed to a high-fat diet (HFD) for 16 weeks to induce obesity. Expression of TLR-3 was significantly higher in human adipocytes compared to the non-adipocyte cells part of the adipose tissue. In vitro, TLR-3 expression was induced during differentiation of adipocytes and stimulation of the receptor led to elevated expression of pro-inflammatory cytokines. In vivo, TLR-3 deficiency did not significantly influence HFD-induced obesity, insulin sensitivity or inflammation. In humans, TLR-3 expression in adipose tissue did not correlate with BMI or insulin sensitivity (HOMA-IR). Together, our results demonstrate that TLR-3 is highly expressed in adipocytes and functionally active. However, TLR-3 appears to play a redundant role in obesity-induced inflammation and insulin resistance.

Danshen is the dried root extract of the plant Salvia Miltiorrhiza and it is used as traditional Chinese medicinal herbal product to prevent and treat atherosclerosis. However, its efficacy has not been thoroughly investigated. This study evaluates the effect of Danshen on hyperlipidemia and hypertension, two well known risk factors for the development of atherosclerosis.This was a randomized, placebo-controlled, double-blind crossover study performed at a tertiary referral center. Participants were recruited by newspaper advertisement and randomized to treatment with Danshen (water-extract of the Salvia Miltiorrhiza root) or placebo for 4 consecutive weeks. There was a wash out period of 4 weeks. Of the 20 analysed participants, 11 received placebo first. Inclusion criteria were: age 40-70 years, hyperlipidemia and hypertension. At the end of each treatment period, plasma lipids were determined (primary outcome), 24 hours ambulant blood pressure measurement (ABPM) was performed, and vasodilator endothelial function was assessed in the forearm.LDL cholesterol levels were 3.82±0.14 mmol/l after Danshen and 3.52±0.16 mmol/l after placebo treatment (mean±SE; p

A small subset of coeliac disease (CD) patients experiences persisting or recurring symptoms despite strict adherence to a gluten-free diet (GFD). When other causes of villous atrophy have been excluded, these patients are referred to as refractory celiac disease (RCD) patients. RCD can be divided in two types based on the absence (type I) or presence (type II) of an, usually clonal, intraepithelial lymphocyte population with aberrant phenotype. RCDI usually runs a benign course and may be difficult to be differentiated from uncomplicated, slow responding CD. In contrast, RCDII can be defined as low-grade intraepithelial lymphoma and frequently transforms into an aggressive enteropathy associated T-cell lymphoma with dismal prognosis. This paper describes the clinical characteristics of RCDI and RCDII, diagnostic approach, and the latest insights in treatment options.

OBJECTIVE: Treatment with glucocorticoids and mineralocorticoids has changed congenital adrenal hyperplasia (CAH) from a fatal to a chronic lifelong disease. Long-term treatment, in particular the chronic (over-)treatment with glucocorticoids, may have an adverse effect on the cardiovascular risk profile in adult CAH patients. The objective of this study was to evaluate the cardiovascular risk profile of adult CAH patients. DESIGN: Case-control study. PATIENTS AND MEASUREMENTS: In this case-control study the cardiovascular risk profile of 27 adult CAH patients and 27 controls, matched for age, sex and body mass index was evaluated by measuring ambulatory 24-hour blood pressure, insulin sensitivity (HOMA-IR), lipid profiles, albuminuria and circulating cardiovascular risk markers (PAI-1, tPA, uPA, tPA/PAI-1 complex, hsCRP, adiponectin, IL-6, IL-18 and leptin). RESULTS: 24-Hour systolic (126.3 mmHg±15.5 vs 124.8 mmHg±15.1 in controls, P = 0.019) and diastolic (76.4 mmHg±12.7 vs 73.5 mmHg±12.4 in controls, P

We developed a technique to classify the composition of enhanced aerosol layers as either smoke or sulfuric acid aerosol using extinction spectra from the Stratospheric Aerosol and Gas Experiment III instrument aboard the International Space Station (SAGE III/ISS). This method takes advantage of the different spectral properties of smoke and sulfuric acid aerosol, which is manifest in distinctly different spectral slopes in the SAGE III/ISS data. Herein we demonstrate the utility of this method and present an evaluation of its performance using four case-study events of two moderate volcanic eruptions (2018 Ambae eruption and 2019 Ulawun eruption, both of which released <0.5 Tg of SO2) and two large wildfire events (2017 Canadian pyroCb and 2020 Australian pyroCb). We provide corroborative data from the Cloud–Aerosol Lidar with Orthogonal Polarization (CALIOP) instrument to support these classifications. This method correctly classified smoke and sulfuric acid plumes in the case-study events >81 % and >99.5 % of the time, respectively. The application of this method to a large volcanic event (i.e., the 2019 Raikoke eruption; ≥1.5 Tg SO2) serves as an example of why this method is limited to small and moderate volcanic events as it incorrectly classified Raikoke's larger sulfuric acid particles as smoke. We evaluated the possibility of smoke being present in the stratosphere before and after the Raikoke eruption. While smoke was present during this time period it was insufficient to account for the magnitude of smoke classifications we observed. Therefore, while this method worked well for large-scale wildfire events and eruptions that inject less SO2, the size of the aerosol created by the Raikoke eruption was outside the applicable range of this method.

The Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Operations (CALIPSO) mission released version 4.1 (V4) of their lidar level 2 cloud and aerosol data products in November 2016. These new products were derived from the CALIPSO V4 lidar level 1 data, in which the calibration of the measured backscatter data at both 532 and 1064 nm was significantly improved. This paper describes updates to the V4 level 2 cloud–aerosol discrimination (CAD) algorithm that more accurately differentiate between clouds and aerosols throughout the Earth's atmosphere. The level 2 data products are improved with new CAD probability density functions (PDFs) that were developed to accommodate extensive calibration changes in the level 1 data. To enable more reliable identification of aerosol layers lofted into the upper troposphere and lower stratosphere, the CAD training dataset used in the earlier data releases was expanded to include stratospheric layers and representative examples of volcanic aerosol layers. The generic “stratospheric layer” classification reported in previous versions has been eliminated in V4, and cloud–aerosol classification is now performed on all layers detected everywhere from the surface to 30 km. Cloud–aerosol classification has been further extended to layers detected at single-shot resolution, which were previously classified by default as clouds. In this paper, we describe the underlying rationale used in constructing the V4 PDFs and assess the performance of the V4 CAD algorithm in the troposphere and stratosphere. Previous misclassifications of lofted dust and smoke in the troposphere have been largely improved, and volcanic aerosol layers and aerosol layers in the stratosphere are now being properly classified. CAD performance for single-shot layer detections is also evaluated. Most of the single-shot layers classified as aerosol occur within the dust belt, as may be expected. Due to changes in the 532 nm calibration coefficients, the V4 feature finder detects ∼9.0 % more features at night and ∼2.5 % more during the day. These features are typically weakly scattering and classified about equally as clouds and aerosols. For those tropospheric layers detected in both V3 and V4, the CAD classifications of more than 95 % of all cloud and daytime aerosol layers remain unchanged, as do the classifications of ∼89 % of nighttime aerosol layers. Overall, the nighttime net cloud and aerosol fractions remain unchanged from V3 to V4, but the daytime net aerosol fraction is increased by about 2 % and the daytime net cloud fraction is decreased by about 2 %.

OBJECTIVE: To determine the efficacy, impact on quality of life (QOL) and safety of prucalopride, a selective, high-affinity 5-HT4receptor agonist, in patients with chronic constipation. METHODS: In this multicentre, randomised, placebo controlled, parallel-group, phase III study, patients with chronic constipation (two or fewer spontaneous complete bowel movements (SCBM)/week) received 2 mg or 4 mg prucalopride or placebo, once daily, for 12 weeks. The primary efficacy endpoint was the proportion of patients reaching three or more SCBM/week. The key secondary efficacy endpoint was the proportion of patients having an increase of one or more SCBM/week. The primary QOL endpoint was the patient assessment of constipation QOL satisfaction subscale score. Safety parameters included adverse events, laboratory values and cardiovascular events. RESULTS: Efficacy was evaluated over 713 patients. Averaged over 12 weeks, higher proportions of patients on prucalopride 2 mg (19.5%; p<0.01), 4 mg (23.6%; p<0.001) had three or more SCBM/week (or normalisation of bowel function) compared with placebo (9.6%). Similar results were seen in the subgroup (83%) of patients dissatisfied with previous laxative treatment. Both doses of prucalopride also significantly improved secondary efficacy and QOL endpoints, including the proportion of patients with an increase of one or more SCBM/week, evacuation completeness, perceived disease severity and treatment effectiveness and QOL. Prucalopride 4 mg significantly reduced the need for straining versus placebo (p<0.05). The most frequent treatment-related adverse events were headache and diarrhoea. Both doses of prucalopride were safe and well tolerated. CONCLUSION: Prucalopride significantly and consistently improved bowel function, associated symptoms and satisfaction in chronically constipated patients. TRIAL REGISTRATION NUMBER: NCT00488137. [ABSTRACT FROM AUTHOR]

Ischaemia, like muscle contraction, has been reported to induce skeletal muscle glucose uptake in in vitro models. This stimulating effect appears independent of insulin and is probably mediated by activation of AMPK (AMP-activated protein kinase). In the present study, we hypothesized that in vivo in humans ischaemia- and insulin-induced glucose uptake are additive, and that the combined impact of ischaemia and contraction on glucose uptake is of a similar magnitude when each is applied separately. We assessed the effects of ischaemia with and without euglycaemic–hyperinsulinaemia (clamp; protocol 1) and with and without muscle contraction (protocol 2) on muscle FGU (forearm glucose uptake) in healthy subjects. Furthermore, we assessed the impact of ischaemia on FBF (forearm blood flow; plethysmography). In protocol 1, ischaemia increased FGU from 0.6±0.1 at baseline to 5.5±1.9 μmol·min−1·dl−1, and insulin increased FGU to 1.6±0.3 μmol·min−1·dl−1 (P<0.05 for both). The combination of ischaemia+insulin increased FGU to 15.5±2.2 μmol·min−1·dl−1 (P<0.05 compared with each stimulus alone). Maximal FBF obtained after ischaemia was similar with and without hyperinsulinaemia. In protocol 2, isometric contraction increased FGU from 0.3±0.1 to 2.7±0.8 μmol·min−1·dl−1 (P<0.05), but FGU was not significantly different from ischaemia compared with ischaemia+contraction. However, combined ischaemia+contraction resulted in a greater increase in FBF. In summary, ischaemia and insulin independently stimulate skeletal muscle glucose uptake in vivo in humans, whereas ischaemia and contraction do not. The observed differential effects of these stimuli on glucose uptake appear to be unrelated to changes in muscle blood flow. [ABSTRACT FROM AUTHOR]

Plasma NEFA (non-esterified fatty acid) concentrations are elevated in patients with obesity. In the present study we first aimed to provide an integral haemodynamic profile of elevated plasma NEFAs by the simultaneous assessment of blood pressure, pulse wave velocity, FBF (forearm blood flow) and sympathetic nervous system activity during acute elevation of NEFAs. Secondly, we hypothesized that NEFA-induced vasodilation is mediated by adenosine receptor stimulation. In a randomized cross-over trial in healthy subjects, Intralipid® was infused for 2 h to elevate plasma NEFAs. Glycerol was administered as the Control infusion. We assessed blood pressure, pulse wave velocity, FBF (using venous occlusion plethysmography) and sympathetic nervous system activity by measurement of noradrenaline and adrenaline. During the last 15 min of Intralipid®/Control infusion, the adenosine receptor antagonist caffeine (90 μg·min−1·dl−1) was administered into the brachial artery of the non-dominant arm. Compared with Control infusion, Intralipid® increased pulse wave velocity, SBP (systolic blood pressure) and pulse pressure, as well as FBF (from 1.8±0.2 to 2.7±0.6 and from 2.3±0.2 to 2.7±0.6 ml·min−1·dl−1 for Intralipid® compared with Control infusion; P<0.05, n=9). Although in a positive control study caffeine attenuated adenosine-induced forearm vasodilation (P<0.01, n=6), caffeine had no effect on Intralipid®-induced vasodilation (P=0.5). In conclusion, elevation of plasma NEFA levels increased pulse wave velocity, SBP and pulse pressure. FBF was also increased, either by baroreflex-mediated inhibition of the sympathetic nervous system or by a direct vasodilating effect of NEFAs. As the adenosine receptor antagonist caffeine could not antagonize the vasodilator response, this response is not mediated by adenosine receptor stimulation. [ABSTRACT FROM AUTHOR]

Background: Recent studies in animals have shown that ghrelin stimulates upper gastrointestinal motility through the vagus and enteric nervous system. The aim of the present study therefore was to simultaneously investigate the effect of administration of ghrelin on upper gastrointestinal motility and to elucidate its mode of action by measuring plasma levels of gastrointestinal hormones in humans. Materials and methods: Nine healthy volunteers (four males; aged 22–35 years) underwent combined antroduodenal manometry and proximal stomach barostat study on two separate occasions at least one week apart. Twenty minutes after the occurrence of phase III of the migrating motor complex (MMC), saline or ghrelin 40 μg was administered intravenously over 30 minutes in a double blind, randomised, crossover fashion. Ghrelin, motilin, pancreatic polypeptide, glucagon, and somatostatin were measured by radioimmunoassay in blood samples obtained at 15–30 minute intervals. The influence of ghrelin or saline on MMC phases, hormone levels, and intraballoon volume was compared using paired t test, ANOVA, and χ² testing. Results: Spontaneous phase III occurred in all subjects, with a gastric origin in four. Administration of ghrelin induced a premature phase III (12 (3) minutes, p<0.001; gastric origin in nine, p<0.05), compared with saline (95 (13) minutes, gastric origin in two). Intraballoon volumes before infusion were similar (135 (13) v 119 (13) ml; NS) but ghrelin induced a longlasting decrease in intraballoon volume (184 (31) v 126 (21) ml in the first 60 minutes; p<0.05). Administration of ghrelin increased plasma levels of pancreatic polypeptide and ghrelin but motilin, somatostatin, and glucagon levels were not altered. Conclusions: In humans, administration of ghrelin induces a premature gastric phase III of the MMC, which is not mediated through release of motilin. This is accompanied by prolonged increased tone of the proximal stomach. [ABSTRACT FROM AUTHOR]

Abstract Gastroesophageal reflux (GER), through the occurrence of gastroesophagopharyngeal reflux (GEPR), is an established cause of several otorhinolaryngological (ORL) manifestations. It has been suggested that unexplained excessive throat phlegm might also be a manifestation of GER, but formal evidence is lacking. The aim of the present study was to investigate the prevalence of GER as well as duodenogastroesophageal reflux (DGER) in consecutive patients with chronic complaints of excessive throat phlegm. Fifty-nine consecutive patients with chronic unexplained excessive throat phlegm, transparent in 33 patients (TTP) and yellow in 26 patients (YTP), underwent gastrointestinal endoscopy, 24-hr dual esophageal pH monitoring, and fiberoptic DGER monitoring. Proximal esophageal DGER monitoring was performed in seven YTP patients and analysis of bile acids in throat phlegm was performed on 16 samples. The effect of high-dose acid suppressive therapy was evaluated at 2-week intervals. Endoscopy and pH monitoring established a diagnosis of pathological GER in 75% of the patients. Pathological DGER was present in 56% of the patients and this was associated with YTP. Proximal DGER exposure was high in all investigated subjects and chemical analysis revealed a median bile acid concentration of 0.184 µM in nine YTP samples and no detectable bile acids in seven TTP samples. After a median of 4 weeks of acid suppressive therapy, most patients improved and 61% became asymptomatic. YTP patients were more likely to require maintenance acid suppressive therapy than TTP patients. Unexplained excessive throat phlegm is a sign suggestive of GER and GEPR, and unexplained yellow throat phlegm a sign suggestive of duodenogastroesophagopharyngeal reflux (DGEPR). [ABSTRACT FROM AUTHOR]

Abstract In a subset of patients with gastroesophageal reflux disease (GERD), symptoms persist in spite of proton pump inhibitor (PPI) therapy. Endoscopic gastroplication (EG) was reported to provide a novel therapeutic option in GERD. To evaluate symptomatic and objective outcome of EG in PPI refractory GERD, consecutive GERD patients with persisting reflux symptoms during at least 2 months double dose PPI were recruited for EG (Endocinch). Exclusion criteria were high-grade esophagitis, Barrett’s esophagus, and hiatal hernia >3 cm. Symptoms and PPI use were evaluated before and 1, 3, and 12 months after the EG; 24-hr pH monitoring off PPI was performed before and after 3 and 12 months. All data are given as mean ± SD and were analyzed by Student’s t test. Twenty patients (10 females; mean age, 45 ± 11 years) were recruited. Under conscious sedation with midazolam (6 ± 2 mg) and pethidine (53 ± 5 mg), a mean of 2.0 ± 0.2 sutures was applied during a procedure time of 33 ± 6 min. Throat ache and mild epigastric pain for up to 3 days after the procedure were the only adverse events. At 3 and 12 months symptom score (11.6 ± 6 vs. 6.4 ± 3.7 [ P 2 -blockers and 1 using cisapride after 3 months. After 12 months only six patients were free of PPI use and pH monitoring was normalized in six patients. We conclude that EG provides short- and medium-term symptomatic and objective relief to a subset of GERD patients refractory to high-dose PPI. [ABSTRACT FROM AUTHOR]

Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is still unclear. Glucose is directed into this pathway by GFAT. Because the activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels can increase significantly and dose-dependently in response to elevated glucose concentrations. In glucosamine-treated 3T3-L1 adipocytes, inhibition of insulin-stimulated glucose uptake was highly correlated with UDP-hexosamine levels (r = -0.992; p < 0.0001 for UDP-GlcNAc and r = -0.996; p < 0.0001 for UDP-GalNAc). Incubation of 3T3-L1 adipocytes with 0.1 μM insulin for 24 h in medium containing 1 and 5 mM glucose increased the rate of glucose uptake by 365% and 175% compared to untreated cells, respectively. This increase was not observed when the cells were incubated for 24 h with insulin in medium containing 10 or 25 mM glucose. However, treatment of cells with insulin and 1, 5, 10, or 25 mM glucose resulted in similar increases in levels of UDP-GlcNAc and UDP-GalNAc that always amounted to approx 30-40% above baseline values. This led us to conclude that despite exposure of adipo-cytes to conditions of extreme and prolonged glucose disposal, the increases in cellular UDP-hexosamines were minimal and not dependent on the extracellular glucose concentration. Taken together, our results are in line with the hypothesis that in glucosamine-treated adipocytes UDP-hexosamines influence insulin-stimulated glucose uptake. However, our observations in glucose-treated adipocytes argue against the possibility that UDP-hexosamines function as a nutrient-sensor, and question the role of the hexosamine biosynthe- sis pathway in the pathogenesis of insulin resistance. [ABSTRACT FROM AUTHOR]

Aims/hypothesisThere is increasing evidence for heterogeneity in type 1 diabetes mellitus (T1D): not only the age of onset and disease progression rate differ, but also the risk of complications varies markedly. Consequently, the presence of different disease endotypes has been suggested. Impaired T and B cell responses have been established in newly diagnosed diabetes patients. We hypothesized that deciphering the immune cell profile in peripheral blood of adults with longstanding T1D may help to understand disease heterogeneity.MethodsAdult patients with longstanding T1D and healthy controls (HC) were recruited, and their blood immune cell profile was determined using multicolour flow cytometry followed by a machine-learning based elastic-net (EN) classification model. Hierarchical clustering was performed to identify patient-specific immune cell profiles. Results were compared to those obtained in matched healthy control subjects.ResultsHierarchical clustering analysis of flow cytometry data revealed three immune cell composition-based distinct subgroups of individuals: HCs, T1D-group-A and T1D-group-B. In general, T1D patients, as compared to healthy controls, showed a more active immune profile as demonstrated by a higher percentage and absolute number of neutrophils, monocytes, total B cells and activated CD4+CD25+ T cells, while the abundance of regulatory T cells (Treg) was reduced. Patients belonging to T1D-group-A, as compared to T1D-group-B, revealed a more proinflammatory phenotype characterized by a lower percentage of FOXP3+ Treg, higher proportions of CCR4 expressing CD4 and CD8 T cell subsets, monocyte subsets, a lower Treg/conventional Tcell (Tconv) ratio, an increased proinflammatory cytokine (TNFα, IFNγ) and a decreased anti-inflammatory (IL-10) producing potential. Clinically, patients in T1D-group-A had more frequent diabetes-related macrovascular complications.ConclusionsMachine-learning based classification of multiparameter flow cytometry data revealed two distinct immunological profiles in adults with longstanding type 1 diabetes; T1D-group-A and T1D-group-B. T1D-group-A is characterized by a stronger pro-inflammatory profile and is associated with a higher rate of diabetes-related (macro)vascular complications.

Abstract Background Hypoglycaemia has been shown to induce a systemic pro-inflammatory response, which may be driven, in part, by the adrenaline response. Prior exposure to hypoglycaemia attenuates counterregulatory hormone responses to subsequent hypoglycaemia, but whether this effect can be extrapolated to the pro-inflammatory response is unclear. Therefore, we investigated the effect of antecedent hypoglycaemia on inflammatory responses to subsequent hypoglycaemia in humans. Methods Healthy participants (n = 32) were recruited and randomised to two 2-h episodes of either hypoglycaemia or normoglycaemia on day 1, followed by a hyperinsulinaemic hypoglycaemic (2.8 ± 0.1 mmol/L) glucose clamp on day 2. During normoglycaemia and hypoglycaemia, and after 24 h, 72 h and 1 week, blood was drawn to determine circulating immune cell composition, phenotype and function, and 93 circulating inflammatory proteins including hs-CRP. Results In the group undergoing antecedent hypoglycaemia, the adrenaline response to next-day hypoglycaemia was lower compared to the control group (1.45 ± 1.24 vs 2.68 ± 1.41 nmol/l). In both groups, day 2 hypoglycaemia increased absolute numbers of circulating immune cells, of which lymphocytes and monocytes remained elevated for the whole week. Also, the proportion of pro-inflammatory CD16+-monocytes increased during hypoglycaemia. After ex vivo stimulation, monocytes released more TNF-α and IL-1β, and less IL-10 in response to hypoglycaemia, whereas levels of 19 circulating inflammatory proteins, including hs-CRP, increased for up to 1 week after the hypoglycaemic event. Most of the inflammatory responses were similar in the two groups, except the persistent pro-inflammatory protein changes were partly blunted in the group exposed to antecedent hypoglycaemia. We did not find a correlation between the adrenaline response and the inflammatory responses during hypoglycaemia. Conclusion Hypoglycaemia induces an acute and persistent pro-inflammatory response at multiple levels that occurs largely, but not completely, independent of prior exposure to hypoglycaemia. Clinical Trial information Clinicaltrials.gov no. NCT03976271 (registered 5 June 2019).

IntroductionDespite optimal treatment, patients with chronic coronary artery disease (CAD) and diabetes mellitus (DM) are at high risk of cardiovascular events, emphasizing the need for new treatment options. The Low-Dose Colchicine 2 (LoDoCo2) trial demonstrated that colchicine reduces cardiovascular risk in patients with chronic CAD. This analysis determines the efficacy of colchicine in patients with chronic CAD and DM as well as the effect of colchicine on the development of new-onset type 2 diabetes mellitus (T2DM).MethodsThe LoDoCo2 trial randomized 5,522 patients to placebo or colchicine 0.5 mg once daily, with a median follow-up of 28.6 months. The primary composite endpoint was cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven revascularization. The effect of its treatment in patients with and without DM was evaluated by including an interaction term in the model.ResultsA total of 1,007 participants (18.2%) had T2DM at baseline. The adjusted hazard ratio (HR) [(95% confidence interval (CI)] for the primary endpoint in the T2DM group was 1.52 (1.15–2.01, p

Objectives To compare the efficacy and safety of linezolid and vancomycin for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in Japan. Methods Patients with nosocomial pneumonia, complicated skin and soft-tissue infections or sepsis caused by MRSA were randomized to receive linezolid (600 mg every 12 h) or vancomycin (1 g every 12 h). Results One hundred patients received linezolid and 51 received vancomycin with outcomes evaluated at the end of therapy (EOT) and at the follow-up (FU), 7–14 days later. At EOT, clinical success rates in the MRSA microbiologically evaluable population were 62.9% and 50.0% for the linezolid and vancomycin groups, respectively; and microbiological eradication rates were 79.0% and 30.0% in the two groups, respectively (P Conclusions Linezolid is as effective as vancomycin for the treatment of MRSA infections and may be more effective than vancomycin in achieving microbiological eradication. Haematological adverse events were reported more frequently in linezolid-treated patients; analysis of laboratory data showed a mild reversible trend towards lower platelet counts. [ABSTRACT FROM AUTHOR]

Abstract In a cohort of adults with type 1 diabetes, we examined the prevalence of hypomagnesemia and the correlation of serum magnesium levels with metabolic determinants, such as glycaemic control (as HbA1c), inflammatory markers and circulating cytokines. Furthermore, we assessed if a surrogate for insulin resistance is essential for the possible association of serum magnesium with metabolic determinants. Individuals with type 1 diabetes, aged above 18 years, were included and clinical characteristics were obtained from questionnaires and clinical records. In venous blood samples we measured cytokines and adipose-tissue specific secretion proteins. Serum magnesium concentrations were measured and correlated with clinical data and laboratory measurements using univariate and multivariate regression models. Hierarchical multiple regression of serum magnesium with insulin resistance was adjusted for diabetes and potential magnesium confounders. The prevalence of hypomagnesemia (serum magnesium levels

BackgroundType 2 diabetes (T2D) is characterized by a decreased insulin sensitivity. Magnesium (Mg2+) deficiency is common in people with T2D. However, the molecular consequences of low Mg2+ levels on insulin sensitivity and glucose handling have not been determined in adipocytes. The aim of this study is to determine the role of Mg2+ in the insulin-dependent glucose uptake.MethodsFirst, the association of low plasma Mg2+ with markers of insulin resistance was assessed in a cohort of 395 people with T2D. Secondly, the molecular role of Mg2+ in insulin-dependent glucose uptake was studied by incubating 3T3-L1 adipocytes with 0 or 1 mmol/L Mg2+ for 24 hours followed by insulin stimulation. Radioactive-glucose labelling, enzymatic assays, immunocytochemistry and live microscopy imaging were used to analyze the insulin receptor phosphoinositide 3-kinases/Akt pathway. Energy metabolism was assessed by the Seahorse Extracellular Flux Analyzer.ResultsIn people with T2D, plasma Mg2+ concentration was inversely associated with markers of insulin resistance; i.e., the lower Mg2+, the more insulin resistant. In Mg2+-deficient adipocytes, insulin-dependent glucose uptake was decreased by approximately 50% compared to control Mg2+condition. Insulin receptor phosphorylation Tyr1150/1151 and PIP3 mass were not decreased in Mg2+-deficient adipocytes. Live imaging microscopy of adipocytes transduced with an Akt sensor (FoxO1-Clover) demonstrated that FoxO1 translocation from the nucleus to the cytosol was reduced, indicting less Akt activation in Mg2+-deficient adipocytes. Immunocytochemistry using a Lectin membrane marker and at the membrane located Myc epitope-tagged glucose transporter 4 (GLUT4) demonstrated that GLUT4 translocation was diminished in insulin-stimulated Mg2+-deficient adipocytes compared to control conditions. Energy metabolism in Mg2+ deficient adipocytes was characterized by decreased glycolysis, upon insulin stimulation.ConclusionsMg2+ increases insulin-dependent glucose uptake in adipocytes and suggests that Mg2+ deficiency may contribute to insulin resistance in people with T2D.

Background: The large inter-individual variability in immune-cell composition and function determines immune responses in general and susceptibility o immune-mediated diseases in particular. While much has been learned about the genetic variants relevant for type 1 diabetes (T1D), the pathophysiological mechanisms through which these variations exert their effects remain unknown. Methods: Blood samples were collected from 243 patients with T1D of Dutch descent. We applied genetic association analysis on >200 immune-cell traits and >100 cytokine production profiles in response to stimuli measured to identify genetic determinants of immune function, and compared the results obtained in T1D to healthy controls. Results: Genetic variants that determine susceptibility to T1D significantly affect T cell composition. Specifically, the CCR5+ regulatory T cells associate with T1D through the CCR region, suggesting a shared genetic regulation. Genome-wide quantitative trait loci (QTLs) mapping analysis of immune traits revealed 15 genetic loci that influence immune responses in T1D, including 12 that have never been reported in healthy population studies, implying a disease-specific genetic regulation. Conclusions: This study provides new insights into the genetic factors that affect immunological responses in T1D. Funding: This work was supported by an ERC starting grant (no. 948207) and a Radboud University Medical Centre Hypatia grant (2018) to YL and an ERC advanced grant (no. 833247) and a Spinoza grant of the Netherlands Association for Scientific Research to MGN CT received funding from the Perspectief Biomarker Development Center Research Programme, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). AJ was funded by a grant from the European Foundation for the Study of Diabetes (EFSD/AZ Macrovascular Programme 2015). XC was supported by the China Scholarship Council (201706040081).

Abstract Introduction Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem worldwide. Inflammation plays an important role in disease pathogenesis and recent studies have shown a potential role for the neutrophil serine proteases (NSPs) proteinase-3 (PR3) and neutrophil elastase (NE) in NAFLD as well as an imbalance between NSPs and their natural inhibitor alpha-1 antitrypsin (AAT). The aim of this study was to investigate whether PR3 and NE plasma concentrations are associated with NAFLD and/or type 2 diabetes. Methods To explore this hypothesis we used several cohorts: a cohort of 271 obese individuals with liver steatosis, a cohort of 41 patients with biopsy-proven NAFLD, a cohort of 401 obese type 2 diabetes patients and a cohort of 205 lean healthy controls; and measured PR3 and NE plasma concentrations. In addition, we measured AAT plasma concentrations in order to investigate if the ratios between NSPs and their natural inhibitor were altered in NAFLD and type 2 diabetes when compared to healthy controls. Results Our data shows an increase in PR3 and NE concentrations and a decrease in AAT concentrations in obese patients when compared to controls. Moreover, PR3 plasma concentrations are increased in patients with liver steatosis. Furthermore, PR3 and NE concentrations in the liver are associated with the advanced stages of NAFLD characterized by NASH and/ or liver fibrosis. Additionally, PR3 and NE concentrations were up-regulated in patients with type 2 diabetes when compared to lean and obese controls. Conclusion We conclude that circulating levels of NSPs associate with obesity-related metabolic disorders. Further research is needed to clearly establish the role of these proteases and investigate whether they could be used as non-invasive markers for NAFLD and/or type 2 diabetes.

ObjectivePeople with type 2 diabetes on insulin are at risk for hypoglycemia. Recurrent hypoglycemia can cause impaired awareness of hypoglycemia (IAH), and increase the risk for severe hypoglycemia. The aim of this study was to assess the prevalence and determinants of self-reported IAH and severe hypoglycemia in a Dutch nationwide cohort of people with insulin-treated type 2 diabetes.Research design and methodsObservational study of The Dutch Diabetes Pearl, a cohort of people with type 2 diabetes treated in primary, secondary and tertiary diabetes care centers. The presence of IAH and the occurrence of severe hypoglycemia in the past year, defined as an event requiring external help to recover, were assessed using the validated Dutch version of the Clarke questionnaire. In addition, clinical variables were collected including age, diabetes duration, hemoglobin A1c, ethnicity and education.Results2350 people with type 2 diabetes on insulin were included: 59.1% men, mean age 61.1±10.4 years, mean diabetes duration 14.8±9.2 years and 79.5% on basal-bolus therapy. A total of 229 patients (9.7%) were classified as having IAH and 742 patients (31.6%) reported severe hypoglycemia. Increased odds for IAH were found with complex insulin regimens and lower odds with having a partner and body mass index ≥30 kg/m2. Severe hypoglycemia was associated with complex insulin regimens, non-Caucasian ethnicity and use of psychoactive drugs, and inversely with metformin use.ConclusionsIn this nationwide cohort, almost one out of ten people with type 2 diabetes on insulin had IAH and >30% had a history of severe hypoglycemia in the past year.

Introduction Sex differences in cardiometabolic risk factors and their management in type 2 diabetes (T2D) have not been fully identified. Therefore, we aimed to examine differences in cardiometabolic risk factor levels, pharmacological treatment and achievement of risk factor control between women and men with T2D.Research design and methods Cross-sectional data from the Dutch Diabetes Pearl cohort were used (n=6637, 40% women). Linear and Poisson regression analyses were used to examine sex differences in cardiometabolic risk factor levels, treatment, and control.Results Compared with men, women had a significantly higher body mass index (BMI) (mean difference 1.79 kg/m2 (95% CI 1.49 to 2.08)), while no differences were found in hemoglobin A1c (HbA1c) and systolic blood pressure (SBP). Women had lower diastolic blood pressure (−1.94 mm Hg (95% CI −2.44 to −1.43)), higher total cholesterol (TC) (0.44 mmol/L (95% CI 0.38 to 0.51)), low-density lipoprotein cholesterol (LDL-c) (0.26 mmol/L (95% CI 0.22 to 0.31)), and high-density lipoprotein cholesterol (HDL-c) sex-standardized (0.02 mmol/L (95% CI 0.00 to 0.04)), and lower TC:HDL ratio (−0.29 (95% CI −0.36 to −0.23)) and triglycerides (geometric mean ratio 0.91 (95% CI 0.85 to 0.98)). Women had a 16% higher probability of being treated with antihypertensive medication in the presence of high cardiovascular disease (CVD) risk and elevated SBP than men (relative risk 0.84 (95% CI 0.73 to 0.98)), whereas no sex differences were found for glucose-lowering medication and lipid-modifying medication. Among those treated, women were less likely to achieve treatment targets of HbA1c (0.92 (95% CI 0.87 to 0.98)) and LDL-c (0.89 (95% CI 0.85 to 0.92)) than men, while no differences for SBP were found.Conclusions In this Dutch T2D population, women had a slightly different cardiometabolic risk profile compared with men and a substantially higher BMI. Women had a higher probability of being treated with antihypertensive medication in the presence of high CVD risk and elevated SBP than men, and were less likely than men to achieve treatment targets for HbA1c and LDL levels.

Background Low‐grade inflammation, largely mediated by monocyte‐derived macrophages, contributes to atherosclerosis. Sedentary behavior is associated with atherosclerosis and cardiovascular diseases (CVD). We examined whether reducing sedentary behavior and improving walking time improves monocyte inflammatory phenotype in subjects with increased cardiovascular risk. Methods and Results Across 2 waves, 16 individuals with increased cardiovascular risk performed a 16‐week intervention study (age 64±6 years, body mass index 29.9±4.3 kg/m2), using a device with vibration feedback to promote physical activity. Before and after intervention, we objectively examined physical activity (ActivPAL), cytokine production capacity after ex vivo stimulation in peripheral blood mononuclear cells, metabolism of peripheral blood mononuclear cells, circulating cytokine concentrations, and monocyte immunophenotype. Overall, no significant increase in walking time was found (1.9±0.7 to 2.2±1.2 h/day, P=0.07). However, strong, inverse correlations were observed between the change in walking time and the change in production of interleukin (IL)‐1β, IL‐6, IL‐8, and IL‐10 after lipopolysaccharide stimulation (rs=−0.655, −0.844, −0.672, and −0.781, respectively, all P

Lactate, the end product of anaerobic glycolysis, is produced in high amounts by innate immune cells during inflammatory activation. Although immunomodulating effects of lactate have been reported, evidence from human studies is scarce. Here we show that expression of genes involved in lactate metabolism and transport is modulated in human immune cells during infection and upon inflammatory activation with TLR ligands in vitro, indicating an important role for lactate metabolism in inflammation. Extracellular lactate induces metabolic reprogramming in innate immune cells, as evidenced by reduced glycolytic and increased oxidative rates of monocytes immediately after exposure to lactate. A short-term infusion of lactate in humans in vivo increased ex vivo glucose consumption of PBMCs, but effects on metabolic rates and cytokine production were limited. Interestingly, long-term treatment with lactate ex vivo, reflecting pathophysiological conditions in local microenvironments such as tumor or adipose tissue, significantly modulated cytokine production with predominantly anti-inflammatory effects. We found time- and stimuli-dependent effects of extracellular lactate on cytokine production, further emphasizing the complex interplay between metabolism and immune cell function. Together, our findings reveal lactate as a modulator of immune cell metabolism which translates to reduced inflammation and may ultimately function as a negative feedback signal to prevent excessive inflammatory responses.

Caspase-1 is known to activate the proinflammatory cytokines IL-1β and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 deficiency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by an increased energy production. Increased feces secretion by caspase-1-deficient mice suggests that lipid malabsorption possibly further reduces adipose tissue mass. In this study we investigated whether caspase-1 plays a role in triglyceride-(TG)-rich lipoprotein metabolism using caspase-1-deficient and wild-type mice. Caspase-1 deficiency reduced the postprandial TG response to an oral lipid load, whereas TG-derived fatty acid (FA) uptake by peripheral tissues was not affected, demonstrated by unaltered kinetics of [3H]TG-labeled very low-density lipoprotein (VLDL)-like emulsion particles. An oral gavage of [3H]TG-containing olive oil revealed that caspase-1 deficiency reduced TG absorption and subsequent uptake of TG-derived FA in liver, muscle, and adipose tissue. Similarly, despite an elevated hepatic TG content, caspase-1 deficiency reduced hepatic VLDL-TG production. Intestinal and hepatic gene expression analysis revealed that caspase-1 deficiency did not affect FA oxidation or FA uptake but rather reduced intracellular FA transport, thereby limiting lipid availability for the assembly and secretion of TG-rich lipoproteins. The current study reveals a novel function for caspase-1, or caspase-1-cleaved substrates, in controlling intestinal TG absorption and hepatic TG secretion.

Chronic low-grade inflammation in adipose tissue often accompanies obesity, leading to insulin resistance and increasing the risk for metabolic diseases. MAP3K8 (TPL2/COT) is an important signal transductor and activator of pro-inflammatory pathways that has been linked to obesity-induced adipose tissue inflammation. We used human adipose tissue biopsies to study the relationship of MAP3K8 expression with markers of obesity and expression of pro-inflammatory cytokines (IL-1β, IL-6 and IL-8). Moreover, we evaluated obesity-induced adipose tissue inflammation and insulin resistance in mice lacking MAP3K8 and WT mice on a high-fat diet (HFD) for 16 weeks. Individuals with a BMI >30 displayed a higher mRNA expression of MAP3K8 in adipose tissue compared to individuals with a normal BMI. Additionally, high mRNA expression levels of IL-1β, IL-6 and IL-8, but not TNF -α, in human adipose tissue were associated with higher expression of MAP3K8. Moreover, high plasma SAA and CRP did not associate with increased MAP3K8 expression in adipose tissue. Similarly, no association was found for MAP3K8 expression with plasma insulin or glucose levels. Mice lacking MAP3K8 had similar bodyweight gain as WT mice, yet displayed lower mRNA expression levels of IL-1β, IL-6 and CXCL1 in adipose tissue in response to the HFD as compared to WT animals. However, MAP3K8 deficient mice were not protected against HFD-induced adipose tissue macrophage infiltration or the development of insulin resistance. Together, the data in both human and mouse show that MAP3K8 is involved in local adipose tissue inflammation, specifically for IL-1β and its responsive cytokines IL-6 and IL-8, but does not seem to have systemic effects on insulin resistance.